Gene Therapy for IGHMBP2-Related Diseases

Phase I/IIa Intrathecal Gene Delivery Clinical Trial for IGHMBP2-Related Diseases

Open-label, single intrathecal injection study of a AAV9 vector carrying the IGHMBP2 gene for IGHMBP2-related diseases.

Study Overview

• Status: Enrolling by invitation
• Conditions: SMARD1; CMT2S
• Intervention / Treatment: Biological: Gene Therapy

• Study Type: Interventional
• Enrollment (Anticipated): 10
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 months to 14 years (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Confirmation of two pathogenic variants in the IGHMBP2 gene from a CLIA-certified lab
• Pre-ambulant (not yet walking and less than 18 months) or ambulant (as defined by the ability to walk 10 meters without assistance) or non-ambulant (inability to walk more than 10 meters unassisted)
• Ability to cooperate with functional assessments as per PI's discretion

Exclusion Criteria:

• Prior participation in a gene or cell therapy program for any kind.
• Immunizations of any kind in the month prior to the study.
• Active infection based on clinical observations
• Serological evidence of HIV infection, or Hepatitis B or C infection
• Diagnosis of (or ongoing treatment for) an autoimmune disease
• Persistent leukopenia or leukocytosis (WBC ≤ 3.5 10^3/μL or ≥ 20.0 10^3/μL) or an absolute neutrophil count < 1.5 10^3/μL
• Abnormal liver function as indicated by an elevated GGT (>2X normal if no other laboratory abnormalities), bilirubin and/or abnormal PT/INR
• Concomitant illness or requirement for chronic drug treatment that in the opinion of the PI creates unnecessary risks for gene transfer
• AAV9 binding antibody titers > 1:50 as determined by ELISA immunoassay performed by Athena Diagnostics
• Abnormal laboratory values in the clinically significant range, based upon normal values in the Nationwide Children's Hospital Laboratory
• Diagnosis of any other systemic illness that increases the risk of gene transfer per the PI's opinion; Has a medical condition or extenuating circumstance that, in the opinion of the PI, might compromise the subject's ability to comply with the protocol required testing or procedures or compromise the subject's well-being, safety, or clinical interpretability
• Any requirement for immune modulatory therapy and for which it would be unsafe for the subject to undergo an appropriate wash out period
• Contraindication for intrathecal injection
• A positive JCV antibody test of >0.40

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Single Intrathecal Delivery	Biological: Gene Therapy; AAV9 carrying the IGHMBP2 gene.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Monitoring for the development of unacceptable toxicity.	Unacceptable toxicity is defined as the occurrence of two or more unexpected Grade III or higher treatment-related toxicities, as defined by CTCAE 5.0.	3 years

Secondary Outcome Measures

Outcome Measure	Time Frame
For pre-ambulant participants, ages less than 18 months, change in the Neuromuscular Gross Motor Outcome (GRO) from baseline	Days 90 and 180, Months 12, 18, 24 and 36
For ambulant participants, change in the 100-meter timed test from baseline	Days 90 and 180, Months 12, 18, 24 and 36
For non-ambulant participants, ages 18 months to 6 years, change in the Neuromuscular Gross Motor Outcome (GRO) from baseline	Days 90 and 180, Months 12, 18, 24 and 36
For non-ambulant participants, ages greater than 6 years, change in the revised upper limb module for SMA (RULM) from baseline	Days 90 and 180, Months 12, 18, 24 and 36

Collaborators and Investigators

• Sponsor: Megan Waldrop
• Collaborators: Alcyone Therapeutics

Publications and helpful links

General Publications

• Grohmann K, Schuelke M, Diers A, Hoffmann K, Lucke B, Adams C, Bertini E, Leonhardt-Horti H, Muntoni F, Ouvrier R, Pfeufer A, Rossi R, Van Maldergem L, Wilmshurst JM, Wienker TF, Sendtner M, Rudnik-Schoneborn S, Zerres K, Hubner C. Mutations in the gene encoding immunoglobulin mu-binding protein 2 cause spinal muscular atrophy with respiratory distress type 1. Nat Genet. 2001 Sep;29(1):75-7. doi: 10.1038/ng703.
• Saladini M, Nizzardo M, Govoni A, Taiana M, Bresolin N, Comi GP, Corti S. Spinal muscular atrophy with respiratory distress type 1: Clinical phenotypes, molecular pathogenesis and therapeutic insights. J Cell Mol Med. 2020 Jan;24(2):1169-1178. doi: 10.1111/jcmm.14874. Epub 2019 Dec 4.
• Guenther UP, Handoko L, Varon R, Stephani U, Tsao CY, Mendell JR, Lutzkendorf S, Hubner C, von Au K, Jablonka S, Dittmar G, Heinemann U, Schuetz A, Schuelke M. Clinical variability in distal spinal muscular atrophy type 1 (DSMA1): determination of steady-state IGHMBP2 protein levels in five patients with infantile and juvenile disease. J Mol Med (Berl). 2009 Jan;87(1):31-41. doi: 10.1007/s00109-008-0402-7. Epub 2008 Sep 18.
• Viguier A, Lauwers-Cances V, Cintas P, Manel V, Peudenier S, Desguerre I, Quijano-Roy S, Vanhulle C, Fradin M, Isapof A, Jokic M, Mathieu-Dramard M, Dieterich K, Petit F, Magdelaine C, Giuliano F, Gras D, Haye D, Nizon M, Magen M, Bieth E, Cances C. Spinal muscular atrophy with respiratory distress type 1: A multicenter retrospective study. Neuromuscul Disord. 2019 Feb;29(2):114-126. doi: 10.1016/j.nmd.2018.10.002. Epub 2018 Oct 31.
• Tomaselli PJ, Horga A, Rossor AM, Jaunmuktane Z, Cortese A, Blake JC, Zarate-Lopez N, Houlden H, Reilly MM. IGHMBP2 mutation associated with organ-specific autonomic dysfunction. Neuromuscul Disord. 2018 Dec;28(12):1012-1015. doi: 10.1016/j.nmd.2018.08.010. Epub 2018 Aug 29.
• Eckart M, Guenther UP, Idkowiak J, Varon R, Grolle B, Boffi P, Van Maldergem L, Hubner C, Schuelke M, von Au K. The natural course of infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1). Pediatrics. 2012 Jan;129(1):e148-56. doi: 10.1542/peds.2011-0544. Epub 2011 Dec 12.
• Cottenie E, Kochanski A, Jordanova A, Bansagi B, Zimon M, Horga A, Jaunmuktane Z, Saveri P, Rasic VM, Baets J, Bartsakoulia M, Ploski R, Teterycz P, Nikolic M, Quinlivan R, Laura M, Sweeney MG, Taroni F, Lunn MP, Moroni I, Gonzalez M, Hanna MG, Bettencourt C, Chabrol E, Franke A, von Au K, Schilhabel M, Kabzinska D, Hausmanowa-Petrusewicz I, Brandner S, Lim SC, Song H, Choi BO, Horvath R, Chung KW, Zuchner S, Pareyson D, Harms M, Reilly MM, Houlden H. Truncating and missense mutations in IGHMBP2 cause Charcot-Marie Tooth disease type 2. Am J Hum Genet. 2014 Nov 6;95(5):590-601. doi: 10.1016/j.ajhg.2014.10.002. Epub 2014 Oct 30.

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 4, 2021
• Primary Completion (ANTICIPATED): November 1, 2026
• Study Completion (ANTICIPATED): November 1, 2028

Study Registration Dates

• First Submitted: November 25, 2021
• First Submitted That Met QC Criteria: December 7, 2021
• First Posted (ACTUAL): December 10, 2021

Study Record Updates

• Last Update Posted (ESTIMATE): February 9, 2023
• Last Update Submitted That Met QC Criteria: February 7, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: IGHMBP2
• Other Study ID Numbers: STUDY00002143

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No